Abuse of methamphetamine (METH) is a pressing public health concern. In animals, METH has been shown to have neurotoxic potential toward brain dopamine (DA) and serotonin (5- HT) neurons. Despite the strengths of the available METH neurotoxicity data in animals, several important questions remain. First, it is not yet known if the neurotoxic effects of METH in nonhuman primates are reversible and, if so, whether normal DA and 5-HT innervation patterns are re-established. Second, it is not known if temperature, which markedly influences METH neurotoxicity in rodents, similarly influences METH neurotoxicity in primates. Third, the possibility has been raised that slowly escalating dose regimens of METH may be without neurotoxic consequences in primates, a possibility that would have direct implications for human METH abusers. Finally, the functional consequences of METH neurotoxicity have not been well characterized. All four of these questions have both scientific importance and direct clinical relevance. As such, they are the focus of the present proposal. The specific aims of project are: 1) To determine whether or not injured DA and 5-HT neurons in METH-treated monkeys regenerate over time and, if so, whether normal patterns of DA and 5-HT innervation are re-established; 2) To study the effects of ambient temperature on substituted amphetamine neurotoxicity in nonhuman primates; 3) To determine if a regimen of METH administration that begins with a low dose and escalates slowly renders monkeys insensitive to the neurotoxic effects of METH; and 4) To ascertain whether or not monkeys treated with a neurotoxic regimen of METH are at increased risk for developing a Parkinsonian syndrome following administration of the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPT). To achieve these aims, a combination of quantitative chemical, anatomic, and behavioral methods will be used. The overall goal of these studies is to better understand the long-term effects of toxic doses of METH on brain DA and 5-HT neurons in nonhuman primates, and to provide a framework for reliably interpreting and anticipating possible deleterious effects of METH abuse in humans.